Our Faculty : Primary Faculty

George P. Munson, Ph.D.

Current Research Interests

Perforin-2 and Innate Immunity

Perforin-2, the product of the MPEG1 gene, is an effector of the innate immune system that limits the spread and proliferation of bacterial pathogens. Its amino-terminus contains a Membrane Attack Complex Perforin (MACPF) domain which is also present in several complement proteins and Perforin-1. Gram-negative bacteria are killed when complement proteins C6-C9 form pores in the bacterial envelope. Cytotoxic T lymphocytes (CTL) and natural killer cells (NK) use Perforin-1 to form lytic pores in the membranes of tumor and virally infected mammalian cells. Recently published images by our late colleague Dr. Eckhard Podack and collaborators suggest that Perforin-2 also polymerizes in membranes to destroy bacterial pathogens (McCormack et al. eLife 2015a). In contrast to complement C6-C9 whose activity is restricted to gram-negative bacteria, the bactericidal activity of Perforin-2 is broad spectrum; efficacious against gram-negative, gram-positive, and acid-fast bacteria. Moreover, most mammalian cells have the capacity to express Perforin-2 and this ability endows both immune and non-immune, tissue forming cells with a frontline defense against pathogenic bacteria. Not surprisingly, Perforin-2 deficient mice are severely immunocompromised and rapidly succumb to infectious diseases. Further illustrating Perforin-2’s ancient yet pivotal role in host defense, we have discovered that evolution has endowed many microbial pathogens with toxins and other effectors to block the expression, activation, and/or deployment of Perforin-2 (McCormack et al. eLife 2015b). We believe that the restoration of Perforin-2 activity would allow a patient’s own cells to successfully clear many types of bacterial infections and provide a solution to the scourge of antibiotic resistance. To this end we are using multidisciplinary approaches to better understand Perforin-2’s activation, intracellular trafficking, mechanism of killing, and crosstalk with other parts of the immune system. We are also characterizing novel toxins that subvert or inhibit the bactericidal activity of Perforin-2 with a particular emphasis on enteric and multidrug resistant pathogens.

Diarrheagenic E. coli and other enteric pathogens

Approximately 1.7 million people, primarily infants and children, perish from diarrheal diseases every year. For citizens of low–income countries diarrheal diseases are among the ten leading causes of death. Although many viral and bacterial pathogens cause diarrhea, enterotoxigenic E. coli (ETEC) is prevalent in low–income nations where it is estimated to kill between 300,000 to 700,000 children and infants each year. Another 280 million people are sickened by ETEC annually including travelers from high income countries. Despite decades of research there are no FDA approved vaccines to prevent ETEC infections. Although some vaccines are currently under development and evaluation, at least one initially promising vaccine has failed in a large scale clinical trial. Genome plasticity and strain heterogeneity is a further obstacle to vaccine development. Thus, the prospects for ETEC vaccines are uncertain. 
 Because gut epithelial cells have the capacity to express Perforin-2, we believe that it could play a substantial role in limiting diarrheal diseases. Unfortunately its ability to do so is thwarted by enteric pathogens that deploy toxins and other effectors to block Perforin-2 activity. For example, we have shown that enteropathognic E. coli (EPEC) and Y. pseudotuberculosis inject an enzyme, Cif, into the cytosol of host cells to block the trafficking of Perforin-2. Likewise we have discovered an ETEC toxin that also blocks the mobilization of Perforin-2; albeit, by a mechanism distinct from that of Cif. As expected (delta)toxin mutants are rapidly killed by Perforin-2 while wild-type ETEC proliferate because they suppress Perforin-2 activity. We are currently working to identify the cellular target of this novel toxin with the overall goal of restoring Perforin-2’s ability to fight infectious diseases.

Multidrug resistant pathogens

The 2013 CDC Threat Report categorizes carbapenem-resistant Enterobacteriaceae (CRE) as an Urgent Threat to public health “that requires urgent and aggressive action.” Because these pathogens are multidrug resistant, they are among the most difficult to treat. They are also prevalent in hospital settings with Klebsiella spp. and E. coli as the most frequent causes of nosocomial (hospital acquired) CRE infections in the United States. One step below CREs on the CDC Threat Scale are multidrug resistant Acinetobacter which are commonly the cause of nosocomial pneumonia and bloodstream infections. The increasing prevalence of CREs and multidrug resistant Acinetobacter may soon lead to untreatable infections. Thus, there is an urgent need for the development of new therapeutic options. To answer this need we are currently exploring multiple strategies to increase the expression and/or effectiveness of Perforin-2 to treat these types of infections.

Pubmed Link